As a medical oncologist specializing in GI and Melanoma—and a member of the speaker bureau for Natera—I’ve had the opportunity to closely follow and contribute to the evolving landscape of circulating tumor DNA (ctDNA). This blog reflects both the emerging science and the clinical dilemmas we face as ctDNA becomes a more actionable tool in oncology practice.
It’s been a big year for circulating tumor DNA—ctDNA, or as some of us affectionately call it, our “molecular Magic 8-ball.” For those of us managing colorectal cancer and melanoma, the data are shifting from mere prognostic fascination to something more dynamic: a real-time feedback loop for smarter, more personalized care. Like the old toy, ctDNA offers a glimpse into what might happen next—only now, it’s grounded in molecular science rather than chance. It’s not just predictive; it’s potentially actionable.
But before we dive into the latest data, let’s rewind a bit.
Where We Started: ctDNA as Prognostic Tool Circulating tumor DNA isn’t new anymore. We’ve known for years that it can act as a molecular footprint—shards of tumor DNA floating in the bloodstream, often weeks or months ahead of what we can see on a scan. In stage II and III colorectal cancer, it’s become increasingly clear that ctDNA status after surgery is the strongest predictor of recurrence risk. Stronger than tumor size, lymph node count, or even your gut feeling after tumor board.
And this isn’t just a colorectal phenomenon. In post-surgical solid tumors like triple-negative breast, ovarian, lung, and bladder cancers, ctDNA is rapidly establishing itself as a prognostic marker—especially when negative. This information may help tailor adjuvant therapy decisions as long as we are consistent within NCCN treatment guidelines, allowing oncologists to modulate intensity based on recurrence risk.
Meanwhile, in the metastatic setting—especially among immunotherapy-responsive tumors like melanoma, non-small cell lung cancer, Merkel cell carcinoma, and MSI-high malignancies—ctDNA offers dynamic insights. Here, ctDNA may help distinguish true responders from those progressing, enabling early intervention or justified treatment de-escalation when appropriate.
ctDNA in Colorectal Cancer: The Case for MRD-Guided Management
Let’s talk about stage II colon cancer. Here, ctDNA is arguably ready for prime time. The DYNAMIC trial showed that ctDNA-guided adjuvant therapy cut chemo use in half without sacrificing outcomes. That’s fewer oxaliplatin-induced neuropathies and less overtreatment—all while keeping recurrence-free survival on par with standard strategies.
Then there’s stage III. Trickier. The retrospective data are compelling: if you’re ctDNA-negative after surgery, your 3-year DFS hovers around 90%, chemo or not. But does that mean we should skip chemo? Not quite. We’re not ready to ditch standard care yet, but we can start having smarter conversations about intensity. Maybe it’s time to rethink full FOLFOX for everyone. Maybe single-agent fluoropyrimidine chemotherapy until we have more clear prospective trials… soon to come (ie CIRCULATE US).
And what about those who are ctDNA-positive? That’s where escalation gets interesting. One idea gaining traction: adding irinotecan. Once dismissed as ineffective in the adjuvant “unselected” setting, it may still have a role in MRD-positive, high-risk “selected” patients. The recent CIRCULATE-Japan and BESPOKE-CRC studies hinted at this. Those who cleared ctDNA with chemo—especially sustained clearance—did just as well as their ctDNA-negative peers. Those who didn’t? Their outcomes were abysmal. We’re talking median DFS measured in months, not years.
In fact, we now think of ctDNA-positive patients post-surgery as falling into three buckets:
Sustained clearance post-chemo: Excellent prognosis.
Transient clearance (ctDNA becomes undetectable, then comes back): Delayed but likely recurrence.
No clearance: Immediate concern; median DFS often <6 months.
This is powerful stuff. We’re not just looking at static staging anymore—we’re watching the tumor’s behavior in real time.
Enter DYNAMIC-III: Still More Questions
Just presented this year at ASCO, DYNAMIC-III (4th presentation) took a swing at stage III colon cancer using ctDNA to guide adjuvant therapy decisions. Patients randomized to ctDNA-guided care often received escalated treatment, including regimens like FOLFOXIRI used in half of the patients (which, let’s be honest, isn’t even standard in this space).
And the result? Despite a higher-risk population and more aggressive chemo in half the patients, ctDNA-guided management didn’t improve recurrence-free survival compared to standard care. That stings a bit. But it also teaches us something: escalation alone may not be the answer. Biology matters. So does timing. And maybe, we just need better systemic options for the MRD-positive population.
On a hopeful note, ctDNA burden—the amount detected—emerged as a strong prognostic marker. All patients received adjuvant chemotherapy, yet outcomes varied dramatically by ctDNA burden. Patients with low ctDNA burden post-op who achieved clearance tended to do exceptionally well, suggesting a favorable prognosis despite initial positivity. In contrast, those with high ctDNA burden fared far worse, even with treatment. So quantity, it turns out, matters—and clearance may modulate that risk meaningfully.
Melanoma and ctDNA: Catching Up, Quickly
Melanoma hasn’t had quite as much ctDNA fanfare, but that’s changing. A smaller but compelling study by Eroglu et al. showed that post-op ctDNA positivity in resected melanoma correlated strongly with recurrence. If ctDNA cleared with immunotherapy, outcomes mirrored those of ctDNA-negative patients.
A larger retrospective series by George Anastas et al presented ASCO 2025 as a poster reinforced this: nearly 200 patients, and ctDNA outperformed traditional clinical factors in predicting recurrence. ctDNA-negative patients—many of them stage IIIB/C—had excellent outcomes. Those who were ctDNA-positive? Almost not if, but when the recurrence occurred!
And in the metastatic space, a fascinating study by Caroline Berkley et al showed that early ctDNA clearance after starting IO correlated with one-year PFS rates of 94%. Those with rising ctDNA? Just 48%.
Real-World Impact: Escalation, De-Escalation, or Just Better Timing
Let’s be honest—we all worry about two things: undertreating pseudo-progression, or overtreating true progression. More often than not, it’s the latter. I’ve seen patients stay on ineffective IO for 2-3 months longer than necessary because we hoped it was pseudo-progression. That’s 2-3 months we could’ve spent pivoting to something else that might work—especially when the options are expanding. Today, for patients progressing on PD-1 therapy, we have a growing armamentarium: targeted therapies, bispecifics, intratumoral agents, TIL therapy, TCR-based cell therapies, and novel combinations under clinical trials. CtDNA could help us time that pivot better—avoiding wasted cycles and maximizing opportunity for the next best move.
CtDNA might help us break that inertia. If the signal’s going up, maybe it’s time to switch. If it’s down, maybe we can ease off. And if it’s gone? Maybe we talk about stopping treatment entirely—especially in those struggling with toxicity.
What This Means Across Tumor Types
Colorectal and melanoma are just the beginning. Lung, breast, bladder, ovarian—each will need to define what ctDNA means in their own context. And that will depend not just on the tests, but on the stage or therapies considered. For example, in pancreatic cancer, the prognosis is so poor across the board that a negative ctDNA test means nothing to me —yet. But as treatments improve, that signal might become more actionable perhaps?
One thing is clear: ctDNA is no longer just a shiny research toy. It’s a tool. A compass. A chance to course-correct or stay the path.
So while we still have more to learn, especially around how to act on ctDNA results, I’m convinced of this: the future of cancer care isn’t just about what we see under the microscope—it’s about what we find floating silently in the blood.
About the author
Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. He brings a wealth of expertise to the complex and challenging world of oncology.
Disclosures:
Dr. Thomas serves as a speaker for Bristol Myers Squibb (BMS), Merck, Ipsen, Natera, Immunocore, Pfizer, and SpringWorks. He also receives industry grants in support of numerous clinical trials.